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Pathogen and commensal immunity compared in a reversible infection model that uncouples immunity from pathogen immune evasion

Applicant Hapfelmeier Siegfried
Number 138452
Funding scheme Project funding (Div. I-III)
Research institution Institut für Infektionskrankheiten Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.09.2012 - 31.08.2015
Approved amount 382'169.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Medical Microbiology

Keywords (6)

Microbiota; Mucosal Immunology; Intestine; Mucosal Infection; Innate Immunity; Pathogenic bacteria

Lay Summary (English)

Lead
Lay summary

Even in good health it is normal to continuously mount a strong intestinal immune response towards the non-pathogenic microbes (the so-called “microbiota”) that always colonize our intestinal tract at enormous densities. This type of immunity is important to contain intestinal microbes, but acts without inflammation, and thereby preserves digestive function and microbial ecology. On the other hand, more virulent pathogenic microbes are typically countered with an inflammatory response that impacts on the host-microbial ecosystem and causes collateral damage to host tissues. Although non-pathogenic and pathogenic bacteria co-exist and can be chemically and structurally very similar, this immune discrimination almost always works: aberrant and persistent inflammatory responses in absence of infection are rare; a life-long stable host-microbiota mutualism is the norm. In this research project, using novel bacterial colonization models, we wish to reveal the early mechanisms during bacterial encounter that determine the resulting type of immunity. The information gained could lead to new ideas to improve vaccines and better understand chronic inflammatory diseases.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
D-Alanine-Controlled Transient Intestinal Mono-Colonization with Non-Laboratory-Adapted Commensal E. coli Strain HS.
Cuenca Miguelangel, Pfister Simona P, Buschor Stefanie, Bayramova Firuza, Hernandez Sara B, Cava Felipe, Kuru Erkin, Van Nieuwenhze Michael S, Brun Yves V, Coelho Fernanda M, Hapfelmeier Siegfried (2016), D-Alanine-Controlled Transient Intestinal Mono-Colonization with Non-Laboratory-Adapted Commensal E. coli Strain HS., in PloS one, 11(3), 0151872-0151872.
Memory CD8+ T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function
Balmer Maria L., Ma Eric H., Bantug Glenn R., Grählert Jasmin, Pfister Simona, Glatter Timo, Jauch Annaïse, Dimeloe Sarah, Slack Emma, Dehio Philippe, Krzyzaniak Magdalena A., King Carolyn G., Burgener Anne-Valérie, Fischer Marco, Develioglu Leyla, Belle Réka, Recher Mike, Bonilla Weldy V., Macpherson Andrew J., Hapfelmeier Siegfried, Jones Russell G., Hess Christoph (2016), Memory CD8+ T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function, in Immunity, 44(6), 1312-1324.
Peracetic Acid Treatment Generates Potent Inactivated Oral Vaccines from a Broad Range of Culturable Bacterial Species.
Moor Kathrin, Wotzka Sandra Y, Toska Albulena, Diard Médéric, Hapfelmeier Siegfried, Slack Emma (2016), Peracetic Acid Treatment Generates Potent Inactivated Oral Vaccines from a Broad Range of Culturable Bacterial Species., in Frontiers in immunology, 7, 34-34.
The maternal microbiota drives early postnatal innate immune development.
Gomez de Agüero Mercedes, Ganal-Vonarburg Stephanie C, Fuhrer Tobias, Rupp Sandra, Uchimura Yasuhiro, Li Hai, Steinert Anna, Heikenwalder Mathias, Hapfelmeier Siegfried, Sauer Uwe, McCoy Kathy D, Macpherson Andrew J (2016), The maternal microbiota drives early postnatal innate immune development., in Science (New York, N.Y.), 351(6279), 1296-302.
Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling
Balmer Maria L., Schürch Christian M., Saito Yasuyuki, Geuking Markus B., Li Hai, Cuenca Miguelangel, Kovtonyuk Larisa V., McCoy Kathy D., Hapfelmeier Siegfried, Ochsenbein Adrian F., Manz Markus G., Slack Emma, Slack Emma, Macpherson Andrew J. (2013), Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling, in Journal of Immunology, 193(10), 5273-5283.

Collaboration

Group / person Country
Types of collaboration
Dr. Roy Curtiss III, The Biodesign Institute Arizona State University PO Box 875401 Tempe, AZ United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Emma Slack, Inst. for Microbiology, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
ProCelipe Cava, Laboratory for Molecular Infection Medicine Sweden, Dept. of Molecular Biology, Umea Sweden (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Michael S. Van Nieuwenhze and Prof. Yves V. Brun, Indiana University, Bloomington Indiana, USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Gemeinsame Jahrestagung 2015 der Schweizerischen Gesellschaften für Intensivmedizin, Infektiologie, Notfall- und Rettungsmedizin, und Spitalhygiene Talk given at a conference The gut microbiota containment controlling a monster (plenary talk) 03.09.2015 Interlaken, Switzerland Hapfelmeier Siegfried;
ESF-EMBO Symposium Symbiomes: Systems Biology of Host-Microbiome Interactions Talk given at a conference In-vivo growth deficiency of fully D-alanine auxotrophic smooth E. coli provides a robust model of sterile live bacterial intestinal colonization 05.06.2015 Pultusk, Poland Hapfelmeier Siegfried; Cuenca Vera Miguelangel;
Keystone Symposium: Gut Microbiota Modulation of Host Physiology: The Search for Mechanism Talk given at a conference Next-Generation Models of Reversible Intestinal Colonization: Probing Mucosal Immunity 01.03.2015 Keystone, Colorado, United States of America Hapfelmeier Siegfried;
ECCB'14 13th European Conference on Computational Biology Poster Early immune discrimination between pathogenic and commensal bacteria: A systems biology approach 07.09.2014 Strasbourg, France Cuenca Vera Miguelangel;
World Immune Regulation Meeting (WIRM) 2014 Poster Differential immune response in an intestinal reversible colonization mouse model 19.03.2014 Davos, Switzerland Cuenca Vera Miguelangel; Hapfelmeier Siegfried;
EMBO Practical course on Computational biology: From genomes to cells and systems Talk given at a conference Interaction Between Intestinal Innate and Adaptive Immunity in a Reversible Gnotobiotic Model 29.09.2013 Nevşehir, Turkey Cuenca Vera Miguelangel;


Awards

Title Year
Assistant professor 2012
Member of the Young Academy of Europe (www.yacadeuro.org) 2012

Associated projects

Number Title Start Funding scheme
169791 In-vivo study of protective intestinal long-term colonization with microbiota-syntrophic strains of Salmonella typhimurium and Citrobacter rodentium 01.02.2017 Project funding (Div. I-III)
145016 Bringing flow cytometry a step further: expanding biomedical research capabilities with an imaging flow cytometer 01.10.2012 R'EQUIP
157702 An apparatus for the real-time analysis of cellular metabolism 01.12.2014 R'EQUIP

Abstract

The research described in this proposal will use a novel reversible intestinal infection model that I recently invented (Hapfelmeier et al., 2010; Science 328:1705-1709) for the detailed study of the differences between intestinal commensal and pathogen immune recognition. In my earlier work this system allowed fully reversible intestinal exposure of germ-free animals with live commensal bacteria so that the bacterial-induced intestinal immunity could be uncoupled from persistent bacterial colonization and studied in the again germ-free system. This permitted detailed quantitative and temporal analysis of host responses to encounters of live commensal bacteria. In the research project described here, the reversible bacterial colonization model will be extended to produce a model of reversible intestinal infection with intestinal pathogenic bacteria to uncouple pathogen immunity from pathogen immune evasion. Most microbes we encounter are commensal bacteria that benignly colonize the intestinal lumen. The immune system is well adapted for host-commensal mutualism, and mutualism breakdown, as in inflammatory bowel disease, is rare. In contrast, pathogenic bacterial encounters are less frequent and countered with anti-pathogen immune defense and inflammation. During infection, the host-pathogen relationship is a competition between anti-bacterial immunity and pathogen immune evasion - the latter is well studied, the former largely in systems where the pathogen proliferates and immune evasion overlays immunity. There is the need to experimentally uncouple pathogen immunity and pathogen immune evasion. Our novel approach to this permits the detailed comparative analysis of pathogen and commensal immune induction and will shed new light on the mechanisms of pathogen versus commensal immune recognition. This knowledge is critical for the design of efficient bacterial vaccines and the understanding of the abnormal immune responses directed against commensal microbes in chronic inflammatory diseases.
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